Wnt signaling is a critical determinant for the maintenance and differentiation of stem/progenitor cells, including trophoblast stem cells during placental development. Hyperactivation of Wnt signaling has been shown to be associated with human trophoblast diseases. However, little is known about the impact and underlying mechanisms of excessive Wnt signaling during placental trophoblast development. In the present work, we observed that two inhibitors of Wnt signaling, secreted frizzled-related proteins 1 and 5 (Sfrp1 and Sfrp5), are highly expressed in the extraembryonic trophoblast suggesting possible roles in early placental development. Sfrp1 and Sfrp5 double knockout mice exhibited disturbed trophoblast differentiation in the placental ectoplacental cone (EPC), which contains the precursors of trophoblast giant cells (TGCs) and spongiotrophoblast cells. In addition, we employed mouse models expressing a truncated β-catenin with exon 3 deletion globally and trophoblast-specifically, as well as trophoblast stem cell lines, and unraveled that hyperactivation of canonical Wnt pathway exhausted the trophoblast precursor cells in the EPC, resulting in the overabundance of giant cells at the expense of spongiotrophoblast cells. Further examination uncovered that hyperactivation of canonical Wnt pathway disturbed trophoblast differentiation in the EPC via repressing Ascl2 expression. Our investigations provide new insights that the homeostasis of canonical Wnt-β-catenin signaling is essential for EPC trophoblast differentiation during placental development, which is of high clinical relevance, since aberrant Wnt signaling is often associated with trophoblast-related diseases.

中文翻译：

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缺少sFRP1和sFRP5的超活化Wnt-β-catenin信号传导通过抑制Ascl2破坏滋养细胞分化

Wnt信号传导是胎盘发育期间维持和分化干/祖细胞（包括滋养层干细胞）的关键决定因素。已经显示出Wnt信号的过度激活与人类滋养细胞疾病有关。然而，关于胎盘滋养细胞发育过程中过量Wnt信号转导的影响及其潜在机制知之甚少。在目前的工作中，我们观察到Wnt信号的两种抑制剂，分泌的卷曲相关蛋白1和5（Sfrp1和Sfrp5）在胚外滋养细胞中高度表达，提示在胎盘早期发育中可能发挥作用。Sfrp1和Sfrp5双敲除小鼠在胎盘外胎盘锥体（EPC）中表现出滋养层分化异常，它包含滋养层巨细胞（TGC）和海绵滋养层细胞的前体。此外，我们采用了小鼠模型来表达具有全球外显子3缺失和特定于滋养层干细胞系的截短的β-catenin，以及滋养层干细胞系，并揭示了规范Wnt通路的过度激活耗尽了EPC中的滋养层前体细胞，从而导致巨细胞的丰度以海绵滋养层细胞为代价。进一步检查发现，经典Wnt途径的过度激活通过抑制Ascl2表达干扰了EPC中的滋养细胞分化。我们的研究提供了新的见解，即规范的Wnt-β-catenin信号的稳态对于胎盘发育过程中EPC滋养细胞的分化至关重要，这具有很高的临床意义，